This second part of the Phase 1a study will enroll six healthy subjects per group, with a primary objective to assess safety and tolerability and a secondary objective to assess dose proportionality.
This Phase 1a trial, which was discussed with the U.S. Food and Drug Administration (FDA) in a pre-Investigational New Drug Application (IND) meeting, was designed to include two single oral doses and potentially up to three additional doses of PXL065.
In Part 1 of the Phase 1a study, which was presented during the 2018 American Association for the Study of Liver Diseases (AASLD) meeting, twelve healthy subjects received a single oral dose of 22.5 mg PXL065 or 45 mg Actos.
In this study, PXL065 was shown to be safe and well-tolerated with no adverse events. Based on the pharmacokinetic (PK) results, modeling predicts that a 15 mg dose of PXL065 may provide a similar exposure of R-pioglitazone as a 45 mg dose of the parent drug, pioglitazone (Actos), which suggests it should show similar efficacy with an improved safety profile, including reduced weight gain and fluid retention.
The University of Florida department of medicine’s endocrinology, diabetes and metabolism division chief Dr Kenneth Cusi said: “Nonalcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide and is the most common chronic liver condition in obese patients with prediabetes or type 2 diabetes mellitus.
“Because the mechanism of action for PXL065 is known to target mitochondrial pyruvate carrier (MPC) inhibition, PXL065 is expected to have beneficial effects on insulin resistance and inflammation, which are key components for treating steatohepatitis in patients with NASH.”
Poxel CEO Thomas Kuhn said: “Shortly after signing the acquisition agreement with DeuteRx for PXL065, the IND for PXL065 was transferred to Poxel, and we subsequentially initiated Part 2 of the Phase 1a study.
“Data generated from this latest study of PXL065, including the PK results and modeling work based on the highest approved dose of pioglitazone, should enable us to establish optimal doses for the next phase of development.”
“The underlying pathophysiological mechanisms that contribute to the development and progression of NAFLD and NASH are highly complex and support the need for the development of novel therapies acting on different targets.
“We believe that addressing a variety of relevant pathways, such as mitochondrial pyruvate carrier (MPC) inhibition with PXL065 and direct adenosine monophosphate-activated protein kinase (AMPK) activation with PXL770, could yield greater success in the treatment of NASH,” continued Thomas Kuhn.
Pioglitazone, a drug approved for the treatment of type 2 diabetes has demonstrated therapeutic efficacy for NASH, even in patients with advanced fibrosis.
Pioglitazone is the only drug recommended for biopsy-proven NASH patients by the Practice Guidelines published by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).
However, its therapeutic use and potential have been limited due to the PPARγ-related side effects of weight gain, bone fractures and fluid retention.
PXL065, a novel patent-protected drug candidate, offers an expected new approach for the treatment of NASH and has the potential to preserve the pharmacological benefits of pioglitazone required for the treatment of NASH, such as a reduction of hepatic steatosis, inflammation, ballooning and fibrosis and could reduce PPARγ agonism and the associated side effects that are thought to be related to S-pioglitazone.
PXL065, formerly DRX-065, is deuterium-stabilized R-pioglitazone. Pioglitazone is the most extensively studied drug for NASH and has demonstrated “resolution of NASH without worsening of fibrosis” in a Phase 4 trial.
Pioglitazone is the only drug recommended for biopsy-proven NASH patients by the Practice Guidelines published by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).1 Pioglitazone’s use for NASH, however, has been limited due to the PPARγ-related side effects, which include weight gain, bone fractures and fluid retention.
Pioglitazone is a 1:1 mixture of two mirror-image compounds (stereoisomers) that interconvert in vivo. Using deuterium, DeuteRx stabilized each stereoisomer and characterized their dramatically different pharmacological properties.
In in vitro studies, PXL065 has been shown to target MPC as an inhibitor. In preclinical models, PXL065 exhibits the anti-inflammatory activity and NASH efficacy associated with pioglitazone with little or no weight gain or fluid retention, side effects which are associated with the S-stereoisomer. Based upon preclinical and Phase 1 results to date, PXL065 is expected to exhibit a better therapeutic profile than pioglitazone for NASH.
PXL770 is a first-in-class direct adenosine monophosphate-activated protein kinase (AMPK) activator. AMPK is a central regulator of multiple metabolic pathways leading to the control of lipid metabolism, glucose homeostasis and inflammation.
Based on its central metabolic role, targeting AMPK offers the opportunity to pursue a wide range of indications to treat chronic metabolic diseases, including diseases that affect the liver, such as non-alcoholic steatohepatitis (NASH).
Source: Company Press Release